We propose to combine data from three large sets of prospective cohort studies to address the following three principal hypotheses: 1. Persons homozygous for the MTHFR C677T polymorphism are at reduced risk of colorectal cancer. 2. Higher intakes and serum levels of folate, vitamins B12, B6 and B2, and lower levels of serum homocysteine, are associated with lower risk of colorectal cancer. 3. The association with the MTHFR C677T polymorphism is modified by consumption of alcoholic beverages, and intake of folic acid, methionine, and vitamins B 12, B6 and B2, and serum levels of folate, homocysteine, and vitamins B 12, B6, and B2. We also propose to address a secondary hypothesis: 4. Homozygosity for the MTHFR A1298C polymorphisms, or compound heterozygosity with the C677T polymorphism, is associated with reduced risk of colorectal cancer. We will accomplish this by analyzing data from three very large sources of prospective data - the Harvard Cohort studies (the Nurses' Health Study, Health Professionals' Follow-up Study, and the Physicians' Health Study), the European Prospective Investigation into Cancer and Nutrition (EPIC), and the Alpha-Tocopherol, Beta-Carotene, Cancer Prevention Study (ATBC). With data on 2700 cases of colorectal cancer, and an equivalent number of controls, we will be able to prospectively assess the relations with dietary intake, plasma levels of folate and vitamins that influence one-carbon metabolism, and effect modification by these of the main effect of the MTHFR polymorphisms. Confirming the association between the MTHFR polymorphism and colorectal cancer risk would greatly bolster the case for a causal interpretation of the observational data indicating that folate is inversely related to colorectal cancer risk. Quantifying the relation of the MTHFR C677T polymorphism to colorectal cancer risk, and potential effect modification by other dietary influences on one-carbon metabolism will be important in determining optimum levels of folate and B vitamin nutriture.